Recent advances in the knowledge of molecular processes in an organism and techniques to study these processes have resulted in improved methods and systems of typing and treating diseases. Research is being carried out in many fields in order to provide and/or improve methods for the treatment of diseases as well as providing and/or improving methods and systems for monitoring the effects of treatments.
The compound 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone is an innovative active ingredient having valuable pharmacological properties, especially for the treatment of oncological diseases, immunologic diseases or pathological conditions involving an immunologic component, or fibrotic diseases.
The chemical structure of this compound is depicted below as Formula A.

The base form of this compound is described in WO 01/27081, the monoethanesulphonate salt form is described in WO 2004/013099 and various further salt forms are presented in WO 2007/141283. The use of this molecule for the treatment of immunologic diseases or pathological conditions involving an immunologic component is being described in WO 2004/017948, the use for the treatment of ontological diseases is being described in WO 2004/096224 and the use for the treatment of fibrotic diseases is being described in WO 2006/067165.
The monoethanesulphonate salt form of this compound presents properties which makes this salt form especially suitable for development as medicament. The chemical structure of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate is depicted below as Formula A1.

Preclinical studies have shown that this compound is a highly potent, orally bioavailable inhibitor of vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs), that suppresses tumor growth through mechanisms inhibiting tumor neovascularization. It has further been shown that this compound inhibits signalling in endothelial- and smooth muscle cells and pericytes, and reduces tumor vessel density.
Furthermore, this compound shows in vivo anti-tumor efficacy in all models tested so far at well tolerated doses. The following Table 1 shows the results of the in vivo anti-tumor efficacy testing in xenograft models and in a syngeneic rat tumor model.
TABLE 1CancerModelEfficacyColorectalHT-29T/C 16% @ 100 mg/kg/dHT-29 largetumor volume reductiontumorsGlioblastomaGS-9L syngeneicT/C 32% @ 50 mg/kg/dratHead and neckFaDuT/C 11% @ 100 mg/kg/dLung (non-small-cell)NCI-H460T/C 54% @ 25 mg/kg/dCalu-6T/C 24% @ 50 mg/kg/dOvarianSKOV3T/C 19% @ 50 mg/kg/dProstate (hormone-PAC-120T/C 34% @ 100 mg/kg/ddependent)RenalCaki-lT/C 13% @ 100 mg/kg/dPancreas (murineRip-Taginterference with tumortransgenic)formationT/C represents the reduction of tumor size in % of the control
This compound is thus for example suitable for the treatment of diseases in which angiogenesis or the proliferation of cells is involved.
This compound is further suitable for the treatment of fibrotic diseases, as described in WO 2006/067165.
Despite much research aiming at developing methods for diagnosis and screening, there remains a need for efficient methods and systems for the monitoring of treatment. Monitoring is not always possible or requires complicated, expensive and/or time-consuming procedures which are often inconvenient for a patient, such as obtaining samples, for instance biopsy samples, from a patient and studying these samples in a laboratory. Radiological analysis of tumor cells is only possible weeks after start of tumor therapy.
Thus, in accordance with WO 2008/127528, methods and procedures are provided to monitor response or determine sensitivity in patients to allow the identification of individualized genetic profiles which will aid in treating diseases and disorders.
In accordance with WO 2008/134526, bladder cancer may be detected by screening for the presence of elevated levels of identified biomarkers in urine samples. This document further describes a method for the diagnosis, prognosis, and monitoring of bladder cancer, such as early or late stage bladder cancer, by detecting in a urine sample from a subject at least one biomarker for bladder cancer identified herein, such as alpha-1B-glycoprotein, haptoglobin, sero transferrin, or alpha-1-antitrypsin. The biomarkers may be detected and, optionally, measured using an agent that detects or binds to the biomarker protein or an agent that detects or binds to encoding nucleic acids, such as antibodies specifically reactive with the biomarker protein or a portion thereof.
Thus, the expression amount of certain cell surface molecules have already been proposed as an indication of a disease or of a treatment thereof.
In accordance with WO 2005/083123, the amount of an expression product of AC133 in a sample from an individual, i.e. the amount of the protein or of its mRNA, is indicative for a disease or for the treatment thereof. This reference further states that the expression of AC133 in untreated cancer patients is significantly higher compared to healthy individuals. There is also shown in the examples that AC133 expression significantly drops when various tumor patients are treated, while the total number of circulating endothelial cells remains essentially the same during the same treatment. In essence, this reference further states that the number of circulating endothelial cells is not always indicative for the status of an individual, while the total amount of AC133 expression product is indicative for said status. Similarly, WO 2004/019864 describes the use of quantitative RT-PCR to identify AC133 as a marker and to diagnose and monitor angiogenesis.
However, no method or system using biomarkers for monitoring the treatment of an individual with the above-mentioned active ingredient 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone or a pharmaceutically acceptable salt thereof, and especially its monoethanesulphonate salt form, when used alone or optionally in combination with further pharmaceutically active ingredients and/or further treatments, such as for example radiotherapy, has been so far described or suggested. No such method or system may also be predicted from the prior art.